Abstract Gastroparesis (delayed gastric emptying) occurs in the absence of mechanical obstruction. Although associated with many diseases, the most frequent cause of gastroparesis is diabetes. We have previously showed that acute hyperglycemia induced by glucose infusion significantly delayed solid gastric emptying in normal rats. To study the prolonged effects of hyperglycemia (subacute and chronic effects of hyperglycemia), we utilized streptozotocin (STZ) induced-diabetic rats (animal model of type I diabetes). To the contrary of acute hyperglycemia, gastric emptying was significantly accelerated in rats 2 weeks after STZ injection, compared to that of vehicle-injected rats. Released ghrelin from the gastric mucosa stimulates primarily vagal afferent, accelerating gastric emptying. The elevated plasma ghrelin level has been shown in rats 2-4 weeks after STZ- injection. Our preliminary study also showed that postprandial plasma ghrelin levels and ghrelin mRNA expression of the stomach were significantly increased 2 weeks after STZ injection, compared to that of vehicle injection. We showed that administration of ghrelin antibody and ghrelin receptor antagonists significantly attenuated the accelerated gastric emptying 2 weeks after STZ injection, suggesting that subacute hyperglycemia accelerates gastric emptying via an increased plasma ghrelin level. It has been suggested that insulin suppresses circulating ghrelin levels. STZ destroys beta cells of pancreas and reduces insulin secretion. Thus, it is likely that hypoinsulinemia may increase plasma ghrelin level, which may accelerates gastric emptying in subacute hypoglycemia. In contrast, gastric emptying was significantly delayed 8 weeks after STZ injection. It has been shown that diabetic autonomic neuropathy develops 6-8 weeks after STZ injection. Thus, delayed gastric emptying observed 8 weeks after STZ injection may be explained by the impaired activity of autonomic nervous system. Our preliminary study showed that plasma ghrelin level was no more elevated 8 weeks after STZ injection. As ghrelin release is positively regulated via vagal efferent, the stimulatory effects of hypoinsulinemia on ghrelin release may be masked by the impaired vagal efferent activity in chronic hyperglycemia. This study was designed to investigate the mechanism of accelerated gastric empting in the early phase of diabetes and delayed gastric empting in the late phase of diabetes, from the view point of ghrelin production and autonomic neuropathy. We will study whether insulin treatment alters ghrelin secretion and prevents the development of autonomic neuropathy resulting in normal gastric emptying in chronic hyperglycemia. PUBLIC HEALTH RELEVANCE: Narrative; Gastroparesis is delayed gastric emptying of either solids or liquids, which occurs in the absence of mechanical obstruction. Although associated with many diseases, the most frequent cause of gastroparesis is diabetes mellitus. About one-half of patients with insulin-dependent (type I) or non insulin-dependent (type II) diabetes have delayed gastric emptying of solid or liquid meals. We will focus on the relationship between ghrelin synthesis and autonomic neuropathy in streptozotocin (STZ)-induced diabetic rats. STZ rats are the animal model of type I (insulin deficiency) diabetes. As we will study the hypothesis that insulin deficiency is an important factor for regulating ghrelin synthesis, we will utilize STZ rats. Our study may clarify the mechanism of accelerated gastric emptying in the early phase of diabetes and delayed gastric emptying in the late phase of diabetes. We hope that our study would contribute to the future's better treatment for diabetic gastroparesis of VA patients.